Medical technology makes use of many different types of imaging in order to assist in the visualization for diagnostic purposes of organs, cells, and other features internal to animal bodies. Among these different types of imaging technologies are: X-ray technology, including Computed Axial Tomography (CAT) scans; ultrasound technology; nuclear technologies, including: Single Photon Emission Computed Tomography (SPECT); Positron Emission Tomography (PET); scintigraphic imaging of cells labeled with radioactive materials; and magnetic resonance imaging (MRI). Each of these technologies is based upon significantly different scientific principles. The present invention relates to MRI, which makes use of magnetism and radiofrequency pulses to provide images of features internal to the bodies of mammals.
Conventional MRI contrast agents work on water outside the cells. Many human pathologies resulting from inherited or mutated genes and subsequent defective proteins are inside the cells. The interactions of these defective proteins having conformational changes with intracellular water in cytoplasm and organelles may be different in diseased cells. The MRI contrast agents of the present invention work on water inside the cells.
Current MRI technology makes use of a complex of gadolinium (Gd) with a single chain anion diethylenetriaminepentaacetate (DTPA) as a contrast agent. Schering AG, for instance, provides MAGNEVIST, an ionic formulation of Gd-DTPA. Amersham Health, Inc. provides OMNISCAN, a nonionic formulation of Gd-DTPA-bismethylamide. Upon intravenous administration, these contrast agents diffuse from the vascular space into extracellular or interstitial space of tissues.
Stem cells have been labeled with magnetic iron oxide nanoparticles (MION) and the paramagnetic iron oxide in the cells has then been tracked by MRI. See, e.g., Arbab, et al., “Efficient Magnetic Cell Labeling with Protamine Sulfate Complexed to Ferumoxides for Cellular MRI”, Blood, 104:1217-1223 (2004). After several cell divisions, the iron concentration in vivo is reduced by dilution with the endogenous iron pool, adversely affecting the signal/noise ratio. Iron also induces susceptibility artifacts in the MR images. Luminescent particles of zinc sulfide-coated cadmium selenide 1.5 to 8 nanometers in diameter, called “quantum dots”, have been used in a similar manner, for tracking implanted stem cells by optical imaging. See, e.g., Dabbousi, et al., “(CdSe)ZnS Core-Shell Quantum Dots: Synthesis and Characterization of a Size Series of Highly Luminescent Nanocrystallites”, J. Phys. Chem. B, 101:9463-9475 (1997). The Dabbousi et al. article is reflective of the state of the art with respect to the preparation and administration of quantum dots. Other transfection agents, e.g. green fluorescent proteins (GFP) are used in stem cell tracking by optical imaging. However, the foreign proteins in GFP-transfected cells are susceptible to immune attack in the body thus shortening their expected lifetimes. In addition, they could only be imaged in small animals, due to lower ability of tissue penetration of emitted light used for optical imaging.